Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Proteins that interact with plasma membrane proteins are thought to affect the spatial distribution of such membrane proteins. These interactions are may be important in regulating the function(s) of membrane proteins, such as neurotransmitter receptors, which control synaptic activity in the central nervous system.
The present invention concerns the discovery of a new family of proteins that are enriched in the mammalian central nervous system and that interact with proteins involved in synaptic function. These proteins are involved in synaptic function, as evidenced by their induction by neuronal activation, such as seizures, visual stimulation, acute cocaine, trauma, and the like. These proteins are collectively termed "synaptic activation proteins."
A novel dendritic protein, termed "Homer", exemplifies the present invention. This protein contains a single, PDZ-like binding domain and binds specifically to the C-termiinus of metabotropic glutamate receptors. Metabotropic glutamate receptors release intracellular calcium by activating phospholipase C, which catalyzes the hydrolysis of membrane phosphoinositides. However, other than containing a PDZ-like domain, the Homer protein does not otherwise resemble known PDZ proteins and has less than 10% sequence identity with the closest PDZ protein. Additionally, the Homer protein is regulated as an immediate early gene. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism to regulate metabotropic glutamate signaling.
The features outlined for the Homer protein characterize a novel family of proteins, synaptic activation proteins, which form the basis for the present invention. Because these proteins are involved in synaptic function, they have particular utilities, for example, in screening assays for drugs that affect synaptic function and are therefore centrally active, as further described below.